White Matter Lesions (WML) of aging are commonly seen on MRI scans and show as diffuse or punctate lesions with a predilection to affect periventricular areas. Several studies have shown that WML are associated with increased risk of falls in older adults, often in the context of decreased information processing speed and depressive mood. It is also becoming evident that these factors are not independent but are significantly interconnected. The clinical overlap in symptoms of increased fall risk and depressed mood in WML of aging may suggest a commonality in neurochemical disturbances, such as altered serotoninergic functioning. Serotonin is widely distributed in the brain with most serotonin producing cell-bodies located in the raphe nuclei of the brainstem. Serotonergic projection fibers that provide cortical innervations loop closely around the frontal horn of the ventricles and the anterior corpus callosum before fanning out to the neocortex. As WML of aging have an anatomic predilection for the periventricular white matter areas, including the periventricular frontal horns, which are also an area of increased density of passing serotoninergic projection fibers, we propose to test the novel hypothesis that strategically located periventricular WML may cause differentiation of cortical serotoninergic projection sites. To test this hypothesis, we propose to use brain PET and MR imaging to assess cortical serotonin activity and WML burden in older adults. A tailored clinical test battery will be employed to explore the functional consequences of serotoninergic denervation on fall risk, mobility, information processing speed, and ratings of depression and anxiety in the presence of WML of aging. The results of this pilot study may provide evidence for serotoninergic influences on fall risk in older adults in the presence of WML. Such finding may augur future studies in selected older adults with high WML burden in which the use of pharmaceutical serotoninergic treatment as a new therapeutic approach for fall prevention would be explored. PUBLIC HEALTH RELEVANCE: Falls are the most common accident-related cause for mortality and morbidity in adults 65 years and older in the United States. White Matter Lesions (WML) in the brain are now recognized as a significant risk factor for falls in older adults but effective therapies are lacking. WML of aging are not only associated with altered mobility functioning but also with changes in mood that can increase fall risk. This research proposal will examine a new hypothesis that strategically located WML can disrupt cortical serotoninergic projection fibers. This may not only provide a new framework to better understand the motor and non-motor comorbidity, but may also auger new pharmacological treatment approaches for this epidemic geriatric condition.